Neurological disorders, which include those that arise spontaneously (e.g., Parkinson's disease (PD) and Alzheimer's disease) and those that result from acute injury to neural tissue, generally result in significant reductions in quality of life for those who develop the disorders. Unfortunately, treatments for such disorders are generally of limited efficacy because of the inability to prevent or even reverse the progressive nature of the disorder and/or the inability to provide an individual having such a disorder with any form of repair of the damage done to the nervous tissue.
Parkinson's disease (PD) remains one of the leading causes of chronic neurological disability, which affects more than 1,500,000 Americans. The incidence rises with age, being approximately 1:1000 overall, but affecting 2% of the population over the age of 65. About 60,000 new cases are reported each year, and in recent years the annual number of deaths from PD has increased steadily (Stahel, 2006). Internationally, the incidence rate for PD approximates 17 per 100,000 per year, although this is probably an underestimate. Parkinson's disease (PD) is characterized by the extensive loss of dopaminergic (DA) neurons in the substantia nigra (SN) in the midbrain (Hornykiewicz, 1973b). Currently the principle treatment for PD is oral L-3,4-dihydroxyphenylalanine (L-dopa), which is the precursor of dopamine that can pass the blood-brain barrier (Hornykiewicz, 1973a).
L-dopa largely provides symptomatic relief, but with time becomes less effective for two reasons. First, during the progression of the disease the neurons become less sensitive to the drug. Second, L-dopa does not delay or diminish degeneration of the DA neurons (Lang & Lozano, 1998). Thus, there continues to be an ongoing need for identifying new strategies for inhibiting or even reversing the progression of PD and other neurological disorders.
Recent research has attempted to identify and isolate cell populations that can be used to replace lost or degenerating dopaminergic neurons (Marshall et al., 2006; Anderson & Caldwell, 2007). An underlying principle of cell replacement therapy is that restoration of function lost as a result of damage or disease in the CNS might be accomplished by the replacement of dead or dying cells with healthy ones. Recent studies further suggest that the engraftment of stem cells or progenitors can up regulate or enhance existing endogenous progenitor populations and possibly rescue damaged cells (Redmond et al., 2007). Other investigators have employed neural cell transplants obtained from the fetal ventral mesencephalic (VM) dopaminergic neurons (Lindvall et al., 1988; Madrazo et al., 1988; Lindvall et al., 1992; Freeman et al., 1995; Borlongan, 2000). However, these transplants frequently lead to troublesome dyskinesia (Freed et al., 2001; Olanow et al., 2003). Even when excellent dopaminergic reinnervation was obtained, which produced positive clinical improvements in the absence of dyskinesia, the amount of tissue required for each PD patient necessitated a minimum of 4-5 fetal brains (Mendez et al., 2005). This requirement increased the possibility of viral or bacteria infection that significantly limited the utility of this approach. In addition, the number of surviving neurons was highly limited as most engrafted cells died (Borlongan, 2000). The limited supply of fetal VM cells coupled with their poor graft survival severely limits the therapeutic utility of this approach for the treatment of PD. Therefore, the identification and isolation of alternate expandable sources of dopaminergic neurons have become a major research focus (Daadi, 2002; Doss et al., 2004; Lindvall et al., 2004) and continues to be an ongoing need.
Thus, there continues to be a need for new approaches to generate populations of transplantable cells suitable for a variety of applications, including but not limited to treating injury and/or disease of neurological tissues.